The human body responds to various injuries by a biological process that involves the remodeling of the ECM, the non-cellular component present in all tissues and organs. Tissue remodeling occurs in a highly regulated and exquisitely choreographed fashion which may lead to the regeneration of the injured tissue recovering its original architecture. However, aberrant tissue remodeling characterized by excessive deposition of ECM components, among many others collagens and fibronectin, may lead to progressive fibrosis accompanied by the destruction of the original tissue architecture and the decline of organ functions. Accordingly, the term of progressive fibrosis is also used in medical sciences to describe the pathological state of excess deposition of fibrous tissue, i.e. a tissue composed of bundles of collagenous white fibers between which rows of connective tissue cells are found. The interaction of multiple pathways, molecules and systems determines whether fibrosis is homeostatic and regenerative, or whether it is uncontrolled and excessive [Pellicoro et al. Nature Reviews Immunology 14, 181-194 (2014)].
Progressive fibrosis is characterized by the excessive production and accumulation of extracellular matrix (ECM) components, including fibrillar collagens (collagen I and III) or collagen IV, which is one of the major components of the basement membrane and glycoproteins (e.g. fibronectin) and proteoglycans (e.g. heparin sulphate) as well. The ECM is a functional tissue whose components possess not only scaffolding characteristics, but also growth facilitating, mitogenic, and other bioactive properties.
In tissue repair, remodeling of the ECM can lead to the regeneration of the tissue when the damaged cells are replaced by other ones to recover the original function of the tissue and the ECM producing myofibroblasts undergo apoptosis. Gradually, the reconstructed ECM takes over the mechanical load again and myofibroblasts disappear. Thus, this regenerative regulatory process counteracts fibrosis which is thereby limited and called herein regenerative remodeling. In “progressive fibrosis” ECM components—particular collagen type I and III and fibronectin—and ECM producing cells continue to accumulate and this process may become adverse or even deleterious to the tissue or to the organ.
Progressive fibrosis occurs when tissue remodeling is shifted towards excessive deposition of ECM leading to destruction of the original tissue architecture and to gradual decline of tissue and/or organ function. Progressive fibrosis is a pathological process leading to the formation of permanent scar tissue; in several cases it causes organ failure and might lead to death [5]. Progressive fibrosis may induce a progressive and continuous loss of organ function in chronic diseases (e.g. fibroproliferative disorders).
The term myofibroblast denotes the co-existence of fibroblast morphological features, such as a developed endoplasmic reticulum (ER) and smooth muscle like features, like contractile actin filament bundles. Differentiated myofibroblasts spindle or stellate-shaped cells, which express α-smooth muscle actin (α-SMA) in their contractile filament bundles (stress fibers) and pre-eminently contribute to ECM remodeling/production. Previously, the derivation of myofibroblast from several other cell types including fibroblasts, stellate cells, pericytes, smooth muscle cells, epithelial, endothelial cells, stem cells or circulating progenitors has been suggested.
Progressive fibrosis may induce a progressive and continuous loss of organ function in chronic fibroproliferative disorders including cardiovascular diseases (cardiac fibrosis associated with acute myocardial infarction (AMI) or hypertension, fibrillation, etc); kidney related diseases, like various forms of chronic kidney diseases (CKD; e.g. diabetic nephropathy, hypertensive nephropathy, obstructive uropathies etc), gastrointestinal diseases (e.g. in inflammatory bowel disease, or esophageal atresia), pulmonary fibrotic diseases (like COPD, asthma or idiopathic pulmonary fibrosis), autoimmune diseases (including SLE, scleroderma, Boeck sarcoidosis), dermal diseases (keloid, scars, acne, or varicella etc), liver cirrhosis or urogenital diseases and many more. The prevalence of these fibroproliferative disorders is rapidly increasing and it has become a major public health problem. Indeed, according to some estimates, about 45% of all deaths are attributed to FD worldwide.
Treatment of these fibroproliferative diseases is not identical with the prevention and/or treatment of the features of progressive fibrosis themselves; fibrosis may even progress further despite or even due to the treatment of the related, possibly causative disease. Quite often pathophysiology of a disease is well or increasingly understood, while that of the accompanying progressive fibrosis is largely unexplored. As Rieder and Fiocchi note in respect of intestinal fibrosis “This ignorance is largely responsible for our current inability to diagnose intestinal fibrosis early and accurately, treat it properly, and take measures to prevent it.” [Rieder et Curr Opin Gastroenterol. July; 24(4), 462-8 (2008)].
Intestinal fibrosis in inflammatory bowel disease: progress in basic and clinical science.
Treatments of Fibrotic Conditions According to the State of the Art
The few classes of compounds, which were thought to be useful in the specific treatment of pathological fibrotic conditions, include compounds having TGFβ inhibitory activity. TGFβ and related factors regulate various cellular proliferation and differentiation processes and are important to organisms for regulating repair and regeneration of cells after tissue disorder. It is known that TGFβ has a role in the accumulation of the ECM proteins and is related to fibrosis of organs or tissues. Neutralizing humanized antibodies targeting TFGβ or its downstream effectors and cooperative regulator CTGF have also been tested [Hutchinson et al. BBA 1832, 962-971 (2013)]. However cautions must be exercised when aiming to target the TGFβ pathway. Indeed TGFβ has a well known tumor-suppressor effect, thus the inhibition of this pathway may provoke the appearance of a subset of malignant tumors. Lack of TGFβ resulted in severe multifocal inflammatory diseases and embrional lethality was observed in TGFβ knockout mice [115] drawing attention to its the strong anti-inflammatory effect and crucial role during development. There might be also some less serious side effects of the manipulation of this pathway like photosensitivity, hepatic dysfunction, dizziness or loss of weight.
In EP 1548008 [SHIMIZU K. et al.] quinoline and quinazoline derivatives having TGFβ inhibitory activity are disclosed.
WO 03/087304A2 [LEE, Wen-Cherng et al.] teaches tri-substituted heteroaryls which are alleged to be potent antagonists of the TGFβ family type receptors, Alk5 and/or Alk4. These compounds are suggested to be useful in the prevention of fibrosis.
Pirfenidone (5-Methyl-1-phenylpyridin-2-one) reduces the production of fibrogenic mediators such as TGFβ and also inhibits TGFβ stimulated collagen production [Schaefer C J et al. Eur Respir Rev 20(120), 85-97 (2011)]. It has anti-fibrotic and anti-inflammatory properties in various in vitro systems and animal models of fibrosis. Cell-based studies have shown that pirfenidone reduces fibroblast proliferation.
Pirfenidone has been approved for treatment in idiopathic pulmonary fibrosis (IPF). In a review by Azuma A. the usefulness and limitations of pirfenidone in IPF treatment are discussed to determine its potential for the management of IPF progression [Azuma A. Expert Review of Respiratory Medicine 4(3), 301-310 (2010)]. It has also been proposed as anti-fibrotic and cytoprotective agent as therapy for progressive kidney disease [M E Cho et al. Expert Opin Investig Drugs. 19(2), 275-283 (2010)], a multicenter, randomized, double-blind placebo-controlled study of pirfenidone (1,800 mg/day) versus placebo was carried out in 107 Japanese patients Clinic with IPF. The primary end point was not significantly different between the two groups [Paz Z et al. Rev Allerg Immunol 38, 276-286 (2010)]. Furthermore pirfenidone cannot be administered to patients with more severe kidney disease (creatinine clearance of less than 30 ml/min) [Armendariz-Borunda J et al. Gut 55(11), 1663-1665 (2006)].
Tranilast (2-{[(2E)-3-(3,4-dimethoxyphenyl)prop-2-enoyl]amino}benzoic acid), an anti-allergic drug was found to be effective in the treatment of keloids and hypertrophic scars resulting from excessive collagen deposition. Recent reports suggest that tranilast reduces pathological fibrosis following AMI via inhibiting myocardial TGFβ1 expression [See F. Heart Lung Circ. 22(2), 122-132 (2013)]. However, while delaying the tranilast commencement of treatment to 7 days post-AMI impeded left ventricular remodeling, intervention from 24 h post-AMI exacerbated infarct expansion.
Maksumova et al. in WO 2010/048716 [Maksumova L. and Unwin D. H.] teach a method in which tranilast or pirfenidone administered together with N-acetyl-cysteine results in an additive anti-proliferative effect, more pronounced than that of either drug alone.
Another treatment concept which may be useful in the treatment of keloids or hypertrophic scars is disclosed by Lee W J et al. [Lee W J et al. Br J Dermatol. 165(3), 673-7 (2011)]. The authors suggest that reduced expression of major ECM components (e.g. type I and III collagen, elastin and fibronectin) shows anti-fibrotic effect of relaxine-expressing adenovirus, which may have therapeutic effects on keloids by reversing pathological fibrosis and preventing keloid recurrence after surgical excision.
New therapeutic targets include e.g. 5-HT antagonists, as 5-Ht2B receptor activation is supposed to play a role in mitogenic signaling. This activity underpins the reason why 5-Ht2B receptor antagonists are treatment options of conditions associated with the development of fibrosis. WO 2009/016227 relates to 5-HT2B antagonist compounds useful in the treatment of fibrotic conditions.
High expression of alpha5beta1 integrin was found in activated fibroblasts with strong accumulation of alpha5beta1 integrin when fibroblasts switch to the fibrotic state. WO 2013/103317 teaches the use of an anti-angiogenic integrin alpha5beta1 inhibitor compound in the treatment of fibrosis and fibrosis-related diseases, demonstrating the effectiveness of the compound in the bleomycin-induced mouse model of pulmonary fibrosis.
CA2368366 describes the beneficial effects of chymase-inhibitor compounds in the Tsk mouse model of scleroderma and the bleomycin-induced mouse model of pulmonary fibrosis.
TNFα ligands are extensively researched potential therapeutics of the disease states characterized by the overproliferation of myofibroblasts and/or excess production of fibrous material. WO 2010/085959 relates to a TNFα antagonist useful in the treatment of radiation-induced fibrosis.
Therapeutically used mesenchymal stem cells were also envisaged to regenerate organs affected by progressive fibrosis by local or systemic administration, however, clinical studies failed to unambiguously prove this concept. Furthermore they are said to be even a potential risk for turning the host environment to fibrogenic rather than regenerative cells. Paz Z and Shoenfeld Y. in 2010 gave a detailed review of treatment options for progressive fibrosis, an admittedly “heavily investigated subject” [Paz Z et al. Clin Rev Allergy Immunol. 38(2-3), 276-286 (2010)]. The authors are moderately optimistic but acknowledge that “No proven antifibrotic therapy has shown efficacy in ameliorating the clinical course of fibrotic diseases, but our current understanding led to the development of different drugs with promising results, like: mycophenolate mofetil, interferon, relaxin, and intravenous immunoglobulin” (emphasis added).
Similarly, Hinz. B and Gabbiani G [Hinz. B et al. F1000 Biol Rep., 2:78 (2010)] after a review of the mechanisms of myofibroblast action and possible strategies for treatment evaluated recent development as “new findings that may develop into therapeutic strategies during the next few years” (emphasis added).
Most recently Karihaloo A. comes to a more gloomy conclusion on anti-fibrosis therapy [Karihaloo A. Curr Diab Rep. 12(4), 414-22 (2012)]: “Research points towards a multifactorial etiology and complex interplay of several pathogenic pathways that can contribute to the declining kidney function in diabetes. Patients with diabetic nephropathy (and with any chronic kidney disease) eventually develop kidney fibrosis. Despite the financial and labor investment spent on determining the basic mechanism of fibrosis, not much progress has been made in terms of therapeutic targets available to us today.”
All these literature data further underline that there is no generally accepted therapy at present for progressive fibrosis in fibroproliferative disorders. Treatment of the underlying, causative or consequential disease is not sufficient to provide a solution and to treat the progressive fibrosis itself. In conclusion, the need to control progressive fibrosis per se thus remains.
The present inventors have unexpectedly found that Sigma-1-receptor (S1R) agonist compounds are useful in the prevention, control and treatment of progressive fibrosis and thereby conditions associated therewith, in particular excessive deposition of ECM, preferably collagen, e.g. collagen type I, III and fibronectin; and/or accumulation of cells producing ECM proteins.